Evidence for the Role of Tetramethylethylenediamine in Aqueous Negishi Cross-Coupling: Synthesis of Nonproteinogenic Phenylalanine Derivatives on Water

Abstract

The structure of the alkylzinc-tetramethylethyl-enediamine (TMEDA) cluster cation 3 has been determined in the gas phase by a combination of tandem mass spectrometry, infrared multiphoton dissociation (IRMPD) spectroscopy, and DFT calculations. Both sets of experimental results establish the existence of a strongly stabilizing interaction of TMEDA with the zinc cation. High-level DFT calculations on the alkylzinc-TMEDA cluster cation 3 allowed the identification of two low energy conformers, each featuring a four-coordinate zinc atom with a bidentate TMEDA ligand, and internal coordination from the carbonyl group of the Boc group to zinc. The experimental IRMPD spectrum is reproduced with an appropriately weighted combination of the IR spectra of the two conformers identified by theory. DFT calculations on the structure of the alkylzinc halide 2 with coordinated TMEDA using the PCM model of water solvent suggest that TMEDA can promote ionization of the zinc-iodine bond in organozinc iodides under aqueous conditions, providing a credible explanation for the role of TMEDA in stabilizing the carbon-zinc bond. Reaction of the serine-derived iodide 1 with aryl iodides "on water", promoted by nano zinc in the presence of PdCl(2)(Amphos)(2) (5 mol %) and TMEDA, leads to the formation of protected phenylalanine derivatives 4 in reasonable yields. In the case of ortho-substituted aryl iodides and aryl iodides that are solids at room temperature, conducting the reaction at 65 °C gives improved results. In all cases, the product 5 of reductive dimerization of the iodide 1 is also isolated.

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…In contrast to these aromatic amino acids bearing (pseudo)halogenated moieties, amino acid-based alkyl halides are not used directly as substrates in the Suzuki-Miyaura reaction. To date, their use is limited to the Negishi reaction of β-iodoalanine, β-iodohomoalanine, and iodobishomoalanine with various aryl iodides, to gain access to non-proteinogenic phenylalanine analogues [66][67][68][69]. For peptides that are prepared by chemical methods, SPPS easily enables the replacement of an aromatic amino acid with a non-natural (pseudo)halogenated analogue.…”

Reactivity of Polar Organometallic Compounds in Unconventional Reaction Media: Challenges and Opportunities

“…Lipshutz and co‐workers have effectively dominated the field of aqueous Negishi‐type cross‐coupling reactions by describing a new technology that allows Pd‐catalysed Zn‐mediated cross‐couplings to be conducted in water and at room temperature, without the need to preform the corresponding organozinc reagent RZnX 79,80. Lipshutz's approach uses homogeneous micellar catalysis within catalytic nanoreactors formed spontaneously upon dissolution of different surfactants (PTS, TPGS, Brij 30, Solutol, SPGS) in water.…”

Carbon–Carbon Bond Forming Reactions Mediated by Organozinc Reagents

“…Finally, the interesting prospect of performing Negishi-like cross-coupling reactions in aqueous media has recently been addressed. Alkyl iodides react in water with vinyl iodides [263], aryl iodides [264], and heteroaryl bromides [265] in the presence of zinc dust, the palladium precursor PdCl 2 (Amphos), TMEDA, and the nanomicelle-forming surfactant PTS (polyoxyethanyl-α-tocopheryl sebacate) to provide the coupling products in good yields. In the case of (E)-alkenyl iodides, as shown with the formation of 364, complete retention of the (E)-configuration is observed, whereas a very slight erosion is noted for (Z)-alkenyl iodides (Scheme 4.83).…”